Tetracyclic compounds and methods of preparing the same



United States Patent 3,321,489 TETRACYCLIC COMPOUNDS AND METHODS OFPREPARING THE SAIWE Marinas Los, Trenton, N..I., assignor to AmericanCyan- 1zi llnid Company, Stamford, Guam, a corporation of awe N0Drawing. Filed June 4, 1964, Ser. No. 372,665 17 Claims. 01. zen-343.2

This invention relates to new organic compounds and methods for thepreparation thereof. More particularly, it relates to novel compoundsuseful in the synthesis of a biologically active steroid moiety andmethods of preparing said compounds.

The compounds of the present invention may be illustrated by thefollowing formula:

wherein R is lower alkyl, R is selected from the group consisting oftertiary butyl and benzyl, C -C is a trivalent radical selected from thegroup consisting of The present compounds are, in general, crystallinesolids which may be crystallized from common organic solvents such as,for example, ether, ethanol, chloroform or mixtures thereof.

The compounds of the present invention are prepared from startingmaterials, such as, for example, 2-lower alkylcyclo-hexane-l,3-diones(compound I of the flowsheet hereinafter) which is reacted withmethylvinyl ketone in the presence of an alkali metal hydroxide inalcohol and adding to this mixture benzene and pyrrolidine to form a1,6oioxo-A -9-loWer alkyl-octalin (II). This material (II) is separatedfrom the mixture and then treated with sodium borohydride (preferablypurified) in alcohol, preferably ethanol, to form a l-hydroxy- 6-oxo-A-9-lower alkyl-octalin (III) which is separated from the mixture. Thisproduct (III) is then converted to l-acyloxy-6-oxo-A -9-loweralkyl-octalin (TV) by reaction of said material (III) with an acylhalide or an acyl anhydride, preferably acetic anhydride, and pyridine.This material (IV) is then separated from the reaction mixture. Reactionof l-acyloxy-6-oxo-9- lower alkyl-A -octalin (IV) with a lower alkylorthoformate, preferably ethyl orthoformate, in the presence of a strongacid catalyst will form new enol others. For example, when ethylorthofonmate is used in the above reaction, 1-acyloxy-6cthoxy-9-loweralkyl-A 'hexahydronaphthalene is formed in quantitative yield. The crudeenol ether (V) l-acyloxy-o-lower alkoxy-9-lower alkyl-A-hexahydronaphthalene may then be hydrogenated catalytically to the newcompound l-acyloxy-6- lower alkoxy-9-lower alkyl-trans-A -octalin (VI),which without purification, is warmed with 50% aqueous acetic acid togive 1-acyloxy-6-oxo-9-lower alkyl-trans-Decalin (VII). The subjectmatter shown hereinafter in the flowsheet as compounds (IV through VII)is described and claimed in my copending application Ser. No. 360,- 404filed Apr. 16, 1964.

The l-acylcxy-.6-oxo-9-lower alkyl-trans-Decalin compound (VII) whenrefluxed with ethylene glycol and p-toluenesulphonic acid in a solvent,yields l-acyloxy-6,6- ethylenedioxy 9-lower alkyl-trans-Decalin (XII)which in turn is readily converted to 6,6-ethylenedioxy-l-hydroxy-9-lower alkyl-trans-Decalin (XIII) by refluxing with an alcoholicsolution of an alkali metal hydroxide, preferably ethanolic potassiumhydroxide.

When a l-hydroxy-6,6-ethylenedioxy-9-lower alkyltrans-Decalin (compoundsXHI) is heated with benzyl chloride and sodium hydride, an excellentyield of the 1- benzyloxy (compounds XIV) derivative is formed. As anexample, l-hydroXy-6,6-ethylenedioxy-9-methyl-trans- Decalin with benzylchloride and sodium hydride yields 1 benzyloxy 6,6 ethylenedioxy 9methyl trans- Decaliu (XIV).

Hydrolysis of the 6,6-alkylenedioxy ketal function of (compounds XIV) isreadily accomplished by warming the ketal with aqueous acetic acid.Mineral acids in an organic solvent miscible with water can also be usedfor the hydrolysis. As an example,1-benzyloxy-6,6-ethylenedioxy-9-methyl-trans-Decalin (compound XIV) whenwarmed with 30% aqueous acetic acid gives an excellent yield ofl-benzyloxy-o-oxo-9-methyl-trans-Decalin (compound XV).

When the compounds, represented by Formula XV, in an inert solvent,preferably chloroform, are treated with bromine in the same solvent, anexcellent yield of the corresponding bromo compound (XVI) is formed. Asan example 1-benzyloxy-6-oxo-9-methyl-trans-Decalin treated with brominein chloroform, gives a good yield ofl-benzyloxy-7ebromo-6-oxo-9-methyl-trans-Decalin.

The bromo derivative (compounds XV-I) are dehydrobrominated in excellentyields by heating under reflux a solution of bromine compound in drydimethylfor-mamide containing anhydrous lithium halide, preferablylithium chloride, and anhydrous lithiumcarbonate in an atmosphere inertto the reactants. Such reaction yields for example l-benzyloxy-6-oxo-9lower alkyl-A' -transoctalin (compounds XVII). When for examplel-benzyloxy-7-bromo-6-oxo-9-methyl-trans-Decalin is dehydrobrominated indimethylformamide in the presence of lithium chloride and lithiumcarbonate, an excellent yield of l-benzyloxy-6-oxo-9-methyl-A-trans-octalin is formed. The subject matter of compounds (XIV throughXVII) is described and claimed in my copending application Ser. No.372,716 filed June 4, 1964.

By a different route shown in the flowsheet hereinafter1-acyloXy-6-oxo-9-lower alkyl-trans-Decalin (VII) of the formula:

COOR' rl admixed with this solution to yield the corresponding bromoderivative, for example, l-lower alkanoyloxy-7- brorno-6-oxo-9-loweralkyl-trans-Decalin (VIH).

Dehydrobromination of this product is carried out by heating a solutionof product (VIII) in dimethylformamide with a lithium halide, preferablylithium chloride, and preferably in the presence of lithium carbonate,thereby yielding the corresponding A' derivative (IX). The latterproduct is hydrolyzed with mild alkali to produce the corresponding 1hydroxy-6-oXo-9-lower alkyl-A' -transoctalin (X).

The 1-t-butoxy-6-oxo-9-lower alkyl A trans-octalin (XI) is formed byreaction of the above-identified l-hydroxy derivative (X) withisobutylene in an inert solvent, preferably methylene chloride, in thepresence of a strong acid catalyst, preferably phosphoric acid-borontrifluoride.

The compounds (VIII through XI) delineated above and shown in thefiowsheet hereinafter are described and claimed in my copendingapplication Ser. No. 372,688 filed June 4, 1964.

The compound fr (XVIII) wherein R and R are as hereinbefore defined isgeneric to (XVII and XI), shown in fiowsheet can be transformed bycondensation with an alkyl formate, preferably ethyl formate, in thepresence of an alkali metal alkoxide, preferably sodium methoxide, in aninert solvent, such as benzene, to the product (XIX). As a specificexample, 1-t-butoxy-6-0xo-9-methyl-A -trans-octalin with ethyl formateand sodium methoxide in benzene gives an excellent yield oftrans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-5-t-butoxy-2-oxo-I-naphthaldehyderepresented generically by compounds XIX of the flowsheet hereinafter.

When compound (XIX) is reacted with B-unsaturated ketones, preferablyvinyl ketones, in the presence of an alkali metal alkoxide, preferablypotassium-t-butoxide, in an inert solvent, preferably t-butanol, underan inert atmosphere, there is formed a compound of the formula (XX) ingood yield. Specifically, when the compound trans 1,2,4a,5,6,7,8,8aoctahydro-4a-methyl-5-t-butoxy- 2-oxo-1-naphthaldehyde is treated withmethylvinyl ketone in t-butanol containing potassium t-butoxide, thereis obtained trans 1,2,4a,5,6,7,8,8a octahydro-4a-methyl-5-tbutoxy-2-oxo-1-(3-oxobutyl)-l-naphthaldehyde also whenmethyl-5-oxo-6-heptenoate is employed, the product is methyltrans-l-formyl 1,2,4a,5,6,7,8,8a octahydro-4amethyl-S-t-butoxy 6 2dioxo-l-naphthaleneheptanoate. When the corresponding benzylether ofcompound (XIX) is used, the products are the corresponding benzylderivatives. Similarly when lower alkyl-4-oxo-5-hexenoate is used in thereaction R" is lower alkyl acetate in compounds represented by Formula(XX) of fiowsheet.

The conversion of compounds represented by (XX) is readily accomplishedby treating a solution of compound (XX) in a water-miscible organicsolvent, preferably dioxan, with an aqueous solution of an alkali metalhydroxide, preferably sodium hydroxide in an inert atmosphere. As anexample, methyl trans-1-formyl-1,2,4a,5,6, 7,8,8a-octahydro-4a-methyl 5benzyloxy-6,2-dioxo-1- naphthalene heptanoate, (Formula XX) on treatmentwith sodium hydroxide in aqueous dioxan yields dl-2,3,4,4a;8,4b,5,6,7,8,8a-decahydro-8afi-methyl 85 benzyloxy-2'oxo-phenanthrene-l-propionic acid, (compounds XXI). Where theabove-mentioned hexenoate is used in the reaction, R for compoundsrepresented by (XXI) is acetic acid.

The reduction of (compounds XXI) to (compounds XXII) is carried out withhydrogen and hydrogenation catalyst, preferably palladium on strontiumcarbonate. Two solvent systems are employed in the reduction. When (XXI,R'" is CH CH COOH 0r CH COOH) is the substrate, water containing onequivalent of an alkali metal hydroxide, preferably sodium hydroxide, isused. When compounds (XXI, R' is H or lower alkyl) is the substrate, aninert solvent, preferably benzene, is used. As a specific example,dl-Sfi-benzyloxy-Z,3,4,4a18, 4ba,5,6,7,8,8a decahydro 8a 8methyl-Z-oxo-phenanthrene-l-propionic acid (XXI, wherein R is CH, R isCH C H and R is CH CH COOH) on reduction with hydrogen in watercontaining one equivalent of sodium hydroxide in the presence ofpalladium on strontium car- 10 dodecahydro Sapmethyl-2-oxo-phenanthrene-1- bonate give dl-8B-benzyloxy2,3,4,4a,,8,4ba,5,6,7,8,8a,9, propionic acid (XXII, wherein R is CH R isCH C H and R is CH CH COOH). Where the corresponding acetic acid analogof (XXI, in which R is CH COOH) is reduced in the hydrogen in water, thecorresponding acetic acid compound (XXII, R is CH COOH) is obtained.

Although the examples above are specific for R is methyl, the processesare equally applicable when R is lower alkyl and the invention includesthe compounds in which R is a lower alkyl radical. The subject matter ofcompound (XIX through XXII) is described and claimed in my copendingapplication Ser. No. 372,690 filed June 4, 1964.

When compound (XXII, wherein R is or -CH COOH, R is lower alkyl and R isbenzyl or tbutyl) is treated with acetic anhydride-sodium acetate, agood yield of (compounds XXIII) or (XXIII A) are produced. As a specificexample the treatment of dl-Sflbenzyloxy 2,3,4,4a B,4ba,5,6,7,8,8a,9,10dodecahydro- Safi-methyl 2 oxo-phenanth-rene-l-propionic acid (in whichR is CH with acetic anhydride and sodium acetate gives in good yielddl-l7a,B-benzyloxy-5-hydroxy-3, 5-seco-4-nor-5 10) ,9( 11)-D-homoestradien-3-oic acid, 3, 5-lactone (XXIII in which R is CHTreatment of (XXII, where R" is CH COOI-I) yields d1-13 loweralkyl-17a-benzyloxy 1,4 bisnor-3,S-seco-S-hydroxy-D- homo-gona-S( 10) ,91 1 )-dien-3-oic acid, 3,5-lactone.

The reduction of compound (XXIII),

wherein R is tertiary butyl or benzyl and R is lower alkyl, withhydrogen and a hydrogenation catalyst, preferably palladium on strontiumcarbonate in an inert solvent, preferably benzene, gives, in excellentyield (XXIV).

wherein R and R are defined as immediately above. As a specific example,dl-17a,;9-benzyloxy-5-hydroxy 3,5-seco-4-nor-5(10),9(11)-D-homoestradien-3-oic acid, 3,5- lactone (XXIII,wherein R is CH on reduction gives 5dl-l7a,fl-benzyloxy-5-hydroXy-3,5-seco 4 nor 5(l0) D-homoestren-3-oicacid, 3,5-lactone (XXIV, wherein R is CH Finally, when (compounds )QCIV)is treated with methyl magnesium halide, preferably the bromide, and thecrude product allowed to stand in a mixture of acetic and hydrochloricacids (compound XXV) of the formula:

wherein R is benzyl and R is lower al-kyl is formed in good yield. Forexample, dl-17a,/3-benzyloxy-5-hydroxy- 3,5-seco-4-nor-5 l)-D-homoestren-3-oic acid, 3,5-lactone (XXIV, wherein R is CH gives ontreatment with methyl magnesium bromide followed by acid a good yield ofdl-19-nor D homotestosterone, benzylether (compound XXV, wherein R is CHAmong the compounds within the scope of the present invention may be,for example, dl-17afi-benzyloxy-5-hydroxy 3,5 seco 4 nor 5(-10),9 (1l) Dhomoestradien-3-oic acid, 3,5-lactone; dl-17afi-t-butyloxy-5-hydroxy 3,5seco 4 nor 5(10),9(ll) D homoestradiene-3-oic acid, 3,5-lactone;d1-17afi-benzy1oxy-13- ethyl 5 hydroxy 3,5 seco 4 nor 5(10),9 (1 1)-D-homogonadiene-B-oic acid, 3,5-lactone; dl 17aB tbutoxy 13 ethyl 5hydroxy 3,5 seco 4 nor- 5(10) ,9 l l)-'D-homogonadiene-3-oic acid,3,5-lactone; dl 17a 8 benzyloxy 5 hydroxy 3,5 seco 4 nor- 5(10)-D-homoestren-3-oic acid, 3,5-lactone; dl-17afi-tbutyloxy 5 hydroxy3,5 seco 4 nor 5(10) D- homoestrene-3-oic acid, 3,5-lactone;dl-17a/3-benzyloxy- 13 ethyl 5 hydroxy 3,5 seco 4 nor 5(1-0) D-homogonene-3-oic acid, 3,5-1actone; dl-l7afi-t-butoXy-13- ethyl 5hydroxy 3,5 seco 4 nor 5(10) D- homogonene-3-oic acid, 3,5-lactone;dl-19-nor-D-homotestosterone, benzyl ether; 17a 3-benzyloxy-13-ethyl-D-homogon-4-ene-3-one, and the like.

The following flowsheet shows the compounds described hereinbefore.

In the above flowsheet R, R are as hereinbefore defined, R is loweralkyl, R" is hydrogen, lower alkyl, lower alkyl acetate or lower alkylpropionate and R' is hydrogen, lower alkyl, acetic acid or propionicacid.

The compound (XXV) can be transformed into the known biologically activecompound dl-19-nor-D-homotestosterone by removing the benzyl blockinggroup. This can be removed by reduction with lithium in liquid ammoniaafter protecting the keto group :as the ethylenedioxy ketal, andsubsequent acid hydrolysis of the ketal.

When the starting material is dl-17a 3-benzyl0xy-5-hydroxy 3,5 seco 4nor 5(10) -D homogonene- 3-oic acid, 3,5-lactone (compound XXIV, whereinR is C H the final product will be dl-l3-ethyl-l9-nor-D-homo-4-gonene-17aB-ol (compound XXV, wherein R is ethyl and R is H).

When dl-17afi-t-butoxy-5-hydroxy-3,S-seco 4 nor 5(lO)-D-homoestren-3-oic acid, 3,5-lactone (compound XXIV, wherein R isCH and R is t-butyl) is treated with methyl magnesium bromide followedby acid, the product is directly dl-l9-nor-D-homotestosterone, thet-butyl blocking group having been removed during the acid treatment.

Similarly, when the starting material is dl-17a,B-tbutoxy 13 ethyl 5hydroxy 3,5 seco 4 nor- 5(l0)-D-homogonene-3-oic acid, 3,5-laotone(compound XXIV, wherein R is C H and R is t-butyl) and it is carriedthrough the identical reaction sequence, the product isdl-13-ethyl-19-nor-D-homo-4-gonene-17afi-ol (compound XXV, wherein R isethyl and R is H).

The following examples describe the use of starting materials, such as2-lower alkyl-cyclohexane-1,3-diones to prepare the present compounds(XXIII to XXV) and subsequently converting the present compounds to thebiologically active d1-19-nor-D-homotestosterone.

EXAMPLE 1 Preparation of 1,6-di0x0-A -9-ethyl-octalin (II) p'hericpressure. Benzene is added to the residue and the distillation continueduntil the temperature of the vapours OCOR' OCOR I 2 R2 R2 R2 R2 R2 OCORIC e) w nt: m e no I II III 0 1 R0 v Ii on R2o C(CH; R2 R2 0003' E R2 CORR2 COR 4- i- R OR 0 I o Q 0 2 O IX i a m XI ii X H a VIII li vII o XVIIIH R2 CH2 C5 H5 Br R2 OCH: 05 H5 2OCH: Cs H5 R2 CH2 C5 35 H R2 CZCOR' 011) *1 L i o O to l [do I H XVI H XIV H XIII XII it is 80 C. indicatingcomplete removal of methanol and water. Benzene is added to bring thevolume of the solution up to the original volume. The solution is cooledin an ice bath and 3 ml. pyrrolidine is added. The solution is heatedunder reflux under a Dean-Stark water separator for 1 hour when no morewater is azeotropically distilling. The solution is cooled in ice,diluted with ether and washed with 100 ml. water containing 15 ml. of a10% hydrochloric acid solution, followed by 100 ml. water. The aqueousphases are combined and washed with 50 ml. ether. The combined organicphases are washed with three 100 ml. portions of water, saturated brine,dried and evaporated. The residue is distilled. The main fraction boilsat 130l35 C. at 0.06 mm. The distillate is crystallized fromether-hexane to yield 46.7 g. of 1,6- dioxo-A -9-ethyl-octalin. Theanalytical sample obtained by recrystallizations from ether-hexane hasmelting point 67.568.5 C.

The l,6-dioxo-A -9-lower alkyl-octalins are prepared by substituting theappropriate 2-lower alkylcyclohexane- 1,3-dione, for theZ-ethylcyclohexane-1,3-dione in the above reaction. For example, the1,6-dioxo-A -9- methyl-octalin and 1,6-dioxo-A -9-propyl-octalin arereadily prepared by this procedure.

EXAMPLE 2 Preparation of 1-hydr0xy-6-ox0-A -9-ethyloctalin (III) To anice-cold stirred solution of 9.6 g. of 1,6-dioxo- A -9-ethyl-octalin in90 ml. absolute ethanol is added 200 mgs. purified sodium borohydride.After 15 minutes, 200 mgs. sodium borohydride is added and after afurther 15 minutes, 160 mgs. sodium borohydride. The stirring andcooling are continued for 15 minutes and then the solution is acidifiedwith glacial acetic acid. The ethanol is removed under reduced pressureand the residue partitioned between chloroform and water. The aqueousphase is washed with chloroform and the combined organic phases Washedwith sodium bicarbonate solution, dried and evaporated. The residue isdistilled, the product, 1-hydroxy-6-oxo-A -9-ethyl-octal-in, boils at165 C. at 0.8 mm. The oil crystallizes and the analytical sample,melting point 88.0-89.5 C. is obtained by recrystallization fromacetone-hexane.

By employing the appropriate l,6-dioxo-A -9-lower alkyl-octalin in theabove reaction, the corresponding 1- hydroxy-6-oxo-A -9-loweralkyl-octalin is produced. For example, thecorresponding-9-methyl-octalin, -9-pr0- pyl-octalin, -9- butyl orisopropyl octalins may be prepared by this procedure.

EXAMPLE 3 Preparation of 1-acet0xy-6-ox0-A -9-ethyl-0ctalin (IV) Amixture of 3.98 g. of l-hydroxy-6-oxo-A -9-ethyloctalin, 10 ml. aceticanhydride and 2 ml. pyridine are heated on a steam bath for 1.5 hours.The solution is then poured into 300 ml. ice water with stirring. Afterstirring for 1 hour, the aqueous mixture is extracted with ether and theether washed with water, saturated sodium bicarbonate solution, driedand evaporated. The l-acetoxy6-oxo-A -9-ethyl-octalin is obtained as acolorless oil, weighing 4.2 g. and is used without further purification.

The above reaction, when conducted with the appropriate1-hydroxy-6-oxo-A 9-lower alkyl-octalin in presence of pyridine and theappropriate acyl anhydride or aroyl halide yields the correspondingl-acyloxy-6-oxo- A -9-lower alkyl-octalin or l-aroyloxy-6-oxo-A -9-lower alkyloctalin, for example, 1-propionyloxy-6-oxo- A -9-propyloctalin or 1-benzoyloxy-6-oxo-A -9- methyl octalin respectively.

EXAMPLE 4 Preparation of 1-acet0xy-6-eth0xy-9-methyl-Ahexahydronaphtlzalene (V) To a solution of 44.4 grams (0.2 mole) ofl-acetoxy- 6-oxo-9-methyl-A -octalin in 44 ml. ethyl orthoformate, 4 ml.absolute ethanol and 200 ml. benzene is added 4 ml. of absolute ethanolsaturated with hydrogen chloride and the mixture is heated underrefluxing conditions for 2 hours. The mixture is cooled, diluted with anequal volume of ether and poured into 300 ml. of 5% sodium hydroxidesolution. After shaking thoroughly, the aqueous phase is discarded. Theorganic phase is washed with water, saturated brine, dried andevaporated. The residue, a yell-ow mobile oil, which can be crystallizedto a colorless hydrosco-pic solid is essentially pure l-acetoxy-6-ethoxy-9-methyl-A -hexahydronaphthalene as determinedspectroscopically. This material is used directly for the preparation of1-acetoxy-6-ethoxy-9-methyl-trans- A -octalin (VI).

EXAMPLE 5 Preparation of 1-acet0xy-6-eth0xy-9-ethyl-A]zexahydronaphthalene (V) The crude 1-acetoxy-6-oxo-A -9-ethyl-octalin(4.2 g.) (Example 3), 5.6 ml. ethyl orthoformate, 1 ml. absoluteethanol, 1 ml. absolute ethanol saturated with hydrogen chloride and ml.benzene are heated under reflux for 2 hours. The solution is cooled,diluted with ether and washed with 100 ml. of a 5% sodium hydroxidefollowed by washing with water and saturated brine. The organic phase isdried and evaporated to yield l-acetoxy- 6-ethoxy-9-ethyl-A-hexahydronaphthalene as a pale yellow oil weighing 4.7 g. This is usedwithout further purification for the preparation of l-acctoxy-6-ethoxy-A9-ethyl-trans-octalin.

In the above Examples 4 and 5, ethyl orthoformate is used, otherorthoformates may also be used such as methyl, propyl, butyl and thelike. Also other strong acid catalysts can be used in place of hydrogenchloride such as sulfuric acid.

When l-benzoyloxy, l-toluoyloxy or l-halobenzoyloxy, -6-oxo-9-loweralky1-A -octalin, prepared as for example, by reactingl-hydroxy-6-oxo-9-lower alkyl- M -octalin with benzoyl chloride or thelike in pyridine, is substituted for l-acetoxy-6-oxo-9-lower alkyl-Aoctalin, the product from the reaction is the correspondingl-benzoyloxy, l-toluoyloxy or l-halobenzoyloxy, -6-ethoxy-9-loweralkyl-A -hexahydronaphthalene. When this starting material is employed,the products (V through IX), illustrated on the flowsheet, have thel-acetoxy group replaced by the l-benzoyloxy, l-toluoyloxy orl-halobenzoyloxy group.

EXAMPLE 6 Preparation of 1-acetoxy-6-ethoxy-9-methyl-trans-A octalin(VI) Preparation of I-acet0xy-6-eth0xy-A -9-ethyl-transoctalin (VI) Thecrude enol ether of Example 5 (4.7 g.) from l-acetoxy-6-oxo-A-9-ethyl-octalin is dissolved in 200 ml. absolute ethanol and 1.0 g. of2% palladium hydroxide on strontium carbonate is added. The catalyst andcompound are reduced with hydrogen at atmospheric pressure. One molarequivalent of hydrogen is absorbed. The catalyst is then removed byfiltration and the solvent evaporated under reduced pressure. Theresidue consisting predominantly of 1-acetoxy-6-ethoxy-A-9-ethyl-transoctalin weighs 4.7 g. and is used without furtherpurification.

Further, employing the procedure set forth in Examples 6 and 7 above andsubstituting an enol ether of the general formula:

DOOR l Where R and R are lower alkyl, for the 1-acetoxy-6-ethoxy-9-methyl-A -hexahydronaphthalene of Example 6 or the1-acetoxy-6-ethoxy-9-ethyl-A -hexahydronaphthalene of Example 7, and Ris a radical selected from the group consisting of hydrogen, loweralkyl, phenyl and substituted phenyl radicals, there is produced acompound of the general formula:

OCOR' al wherein R and R are lower alkyl and R is a radical as describedabove.

EXAMPLE 8 Preparation of I-aceloxy-9-methyl-d-oxo-trans Decalin (VII)Preparation of 1-acetoxy-6-ox0-9-ethyl-trans- Decalin (VII) The crudel-acetoxy-6-ethoxy-A -9-ethyl-trans-octalin (4.7 g.) prepared as inExample 7 is heated on a stream bath with ml. water and 20 ml. glacialacetic acid for 0.5 hour. The solution is cooled, diluted with Water andextracted with ether. The ether is washed with water, saturated sodiumbicarbonate solution, dried and evaporated. The residue ofl-acetoxy-G-oxo-9-ethyl-trans- Decalin weighs 4.1 g. and is used withoutfurther purification.

Using the procedure described in Examples 8 or 9 above and reacting acompound of the formula:

OCOR' 2 I where R and R are lower alkyl and R is selected from the groupconsisting of hydrogen, lower alkyl, phenyl and substituted phenylradicals, with aqueous acetic acid will yield a compound of the formula:

where R and R are as described above.

EXAMPLE 10 Preparation of 1-acet0xy-7-bromo-6-0x0-9-methyltrans-Decalin(VIII) A mixture of l-acetoxy-6,6-ethylenedioxy-9-methyltrans-Decalin(25 g.) and ml. 50% acetic acid are heated on the steambath for 0.5hour. After cooling, the solution is diluted with water and extractedwith ether. The ether is washed with water, saturated sodiumbicarbonate, dried and evaporated. The residue of l-acetoxy-6-oxo-9-methyl-trans-Decalin weighs 20.5 g. The keto acetate isdissolved in ml. chloroform and cooled to 0 C. To the stirred solutionis added dropwise a solution of 15.0 g. of bromine in 75 ml. chloroform.After the addition, the chloroform is removed under reduced pressure andthe residue crystallizes from ether to give 20.85 g. (74% over-all) ofthe bromo ketone. The analytical sample obtained by recrystallizationsof the crude product from acetone-hexane has a melting point 147 148 C.

The compound 1-acetoxy-7-bromo-6-oxo-9-ethyl-trans- Decalin is readilyprepared in good yield by the above procedure employing1-acetoxy-6,6-ethylenedioxy-9-ethyltrans-Decalin in place of the1-acetoxy-6,6-ethylenedioxy- 9-methyl-trans-Decal-in.

EXAMPLE 11 Preparation of 1-acet0xy-6-ox09-methyLA -transoctalin (IX) Amixture of 27.6 g. of 1-acetoxy-7-bromo-6-oxo-9- methyl-trans-Decalin,25 g. dry lithium chloride and 25 g. dry lithium carbonate in 400 ml.dry dimethylformamide are heated at reflux under nitrogen for 2 hours.The solution is cooled, diluted with water and extracted with ether. Theether is washed twice with Water, saturated brine, dried and evaporated.The residue crystallizes completely and weighed 18.0 g. (89%). Thismaterial is sufliciently pure for the next reaction. An analyticalsample obtained by recrystallization from ether-hexane has a meltingpoint 62.5-63.5 C.

This process is also advantageously employed to produce1-acetoxy-6-oxo-9-ethyl-A' -trans-octalin in high yield by simplysubstituting 1-acetoxy-7-bromo-6-oxo-9-ethyltrans Decalin for 1acetoxy-7-bromo-6-oxo-9-methyltrans-Decalin in the reaction.

EXAMPLE 12 Preparation of 1-hydr0xy-6-0x0-9-methyl-N-transoctalin (X) Amixture of 17.4 g. of 1-acetoxy-6-oxo-9-methyl-A trans-octalin in 100ml. ethanol and 50 g. potassium bicarbonate in 150 ml. water are heatedunder reflux for 5.5 hours. The mixture is cooled, diluted with waterand extracted with ether. The ether is washed with water and saturatedbrine, dried and evaporated. The residue is crystallized fromether-hexane to give 10.2 g. of l-hydroxy-6-oxo-9-methyl-A-trans-octalin, melting point 86- 88" C. The analytical sample hasmelting point 88"- 89 C.

Substituting 1-acetoxy-6-oxo-9-ethyl-A"-trans-octalin for1-acetoxy-6-oxo-9-methyl-A' -trans-octalin in good yield.

I 1 EXAMPLE 13 Preparation of 1-t-but0xy-6-ox0-9-methyl-N-transoctalin(XI) To 25 ml. of liquid isobutylene containing 0.5 ml. of 100%phosphoric acid saturated with boron trifluoride is added 5.0 g. of1-hydroxy-6-oxo-9-methyl-A -trans-octalin in 25 ml. dry methylenechloride. The mixture is shaken overnight at room temperature. Aftercooling the mixture in an ice-methanol bath, excess isobutylene isremoved by a stream of dry nitrogen and the residue is dissolved inmethylene chloride. The solution is washed thoroughly with saturatedsodium bicarbonate solution, dried and evaporated. The residue isdissolved in hexane and passed through a plug of neutral alumina.Evaporation of the solvent yielded 5.7 g. (87%) of crystalline t-butylether melting point 7273 C.

The compound of 1-t-butoxy-6-oxo-9-ethyl-A' -transoctalin is prepared inaccordance with the above procedure employing as the starting material1-hydroxy-6- oxo-9-ethyl-A' -trans-octalin in the place of 1-hydroxy-6-oxo-9-methyl-A -trans-octalin.

EXAMPLE 14 Preparation of1-acezoxy-6,6-ethyZenedioxy-9-methyltrans-Decalin (XII The crude1-acetoxy-9-methyl-6-oxo-trans-Decalin derived from 16 grams crude1-acetoxy-6-ethoxy-9-mcthyl- A -hexahydronaphthalene by the series ofreactions described in Examples 4, 6 and 8 without purification of anyintermediates is heated in 250 ml. benzene containing 16 grams ethyleneglycol and 200 mg. p-toluenesulphonic acid under a Dean-Stark waterseparator for 4 hours. The cold benzene solution is diluted with 200 ml.ether and then washed successively with saturated sodium bicarbonatesolution, water and saturated brine. After drying the organic phase, thesolvents are removed under reduced pressure. The residue is diluted withan equal volume of hexane and kept at C. overnight. The crystalline massis removed by filtration and washed with 20 ml. cold hexane. Total yieldof 1-acetoxy-6,6-ethylenedioxy-9-methyl-trans-Decalin is 9.7 grams (57%based on enol ether of Example 4), melting point 116117 C. is obtained.

In the above reaction ethylene glycol is used to protect the keto group,however, other alcohols can be used such as propandiol.

EXAMPLE Preparation 0 1-acet0xy-6,6-ethylenedioxy-Q-ethyltrans-Decalin(XII) A solution of crude 1-acetoxy-6-oxo-9-ethyl-trans- Decalin (2.05g.) prepared as in Example 9 dissolved in 100 ml. benzene containing2.05 g. ethylene glycol and 100 mg. p-toluenesulphonic acid is heatedunder reflux under a Dean-Stark water separator until no more water isazeotropically removed (4.5 hours). The solution is cooled, diluted withether and washed with saturated sodium bicarbonate solution. The organicphase is then washed with water followed by saturated brine, dried andthe solvents removed under reduced pressure. The residue is crystallizedfrom hexane to give 1-acetoxy-6,6- ethylenedioxy-9-ethyl-trans-Decalin.The analytical sample obtained by recrystallizations of the product fromacetone-hexane has a melting point 78.5-79.5 C.

A compound of the formula:

(BCOR 1.2 as exemplified by Examples 14 and 15 above, where R is loweralkyl and R is hydrogen, lower alkyl, phenyl or substituted phenylradical are prepared by reacting a compound of the formula:

(JOOR Preparation of 1-hydr0xy-6,6-ethylenedioxy-9-methyltrans-Decalin(XIII) A mixture of 10.72 grams (0.04 mole) of l-acetoxy-6,6-ethylenedioxy-9-methyl-trans-Decalin, ml. ethanol and 50 ml. 2 Npotassium hydroxide solution are heated under refluxing conditions for 2hours. Most of the ethanol is removed by distillation under reducedpressure, the residue is diluted with water and extracted with ether.The ether is washed with water, saturated brine, dried and evaporated.The residue crystallizes completely to give 7.9 grams (84% yield) of1-hydroxy-6,6-ethylenedioxy-9-methyl-trans-Decalin, melting point 71-72C.

Employing the procedure of this example and substituting a l-acyloxy orl-aroyloxy, -6-ethylenedioxy-9-lower alkyl-trans-Decalin for1-acetoxy-6-ethylenedioxy-9-rnethyl-trans-Decalin will yield thecorresponding l-hydroxy- 6,6-ethylenedioxy 9-lower alkyl-trans-Decalin.The l-hydroxy-6,6-ethylenedioxy-9-ethyl trans Decalin prepared by thismethod is a crystalline solid, melting point 95 96 C.

EXAMPLE 17 Preparation ofI-benzyl0xy-6,6-ethylenedi0xy-9-methyltrans-Decalin (XIV, R =CH Amixture of 63 ml. benzyl chloride, 10.85 g. l-hydroxy 6,6 ethylenedioxy9 methyl trans Decalin (XIII, R is CH and 11.05 g. of a 54% suspensionof sodium hydroxide in mineral oil is stirred and gradually heated. At-125 C. a vigorous exothermic reaction takes place. When the reactionhas subsided, a temperature of C. is maintained for 1 hour. The mixtureis diluted with benzene and filtered. The benzene and excess benzylchloride are removed under reduced pressure and the residue distilled.The product, l-benzyloxy- 6,6-ethylenedioxy-9-methyl-trans-Decalin isdistilled at 176-182 C. at 0.5 mm. (13.0 g.). The product (XIV, R is CHcrystallizes completely and the analytical sample (from hexane) has amelting point 83-83.5 C.

When 1-hydroxy-6,6-ethylenedioxy-9-ethyl-trans-Decalin (XIII, R is C His used in the reaction with benzyl chloride, the product is1-benzyloxy-6,6-ethylenedioxy-9- ethyl-trans-Decalin (XIV wherein R is CH which distills at 182-184 C. at 0.05 mm.

EXAMPLE 18 Preparation of 1-benzyl0xy-6-0xo-9-methyltrans-Decalin (XV, R=CH To a solution of 130 g. of1-benzyloxy-6,6-ethylenedioxy-9-methyl-trans-Decalin (XIV wherein R isCH in 500 ml. glacial acetic acid is added 300 ml. water and the mixtureheated on the steambath for 0.5 hour. Approximately 200 ml. glacialacetic acid are added and the heating continued for 1.5 hours. Aftercooling the mixture, it is diluted with water and extracted with ether.The ether is washed with water, saturated sodium bicarbonate solution,dried and evaporated. The residue is distilled and the product hasboiling point 157 C. and

EXAMPLE 19 Preparation of1-benzyl0xy-7-br0m0-6-0x0-9-methyltrans-Decalin (XVI, R =CH A stirredsolution of 38.35 g. of l-benzyloxy-6-oxo-9- methyl-trans-Decalin in 500ml. chloroform was cooled to and then 25.9 g. of bromine in 175 ml.chloroform is added dropwise at such a rate that there is never morethan a small amount of free bromine present. After the addition, thesolution is poured into a saturated aqueous sodium bicarbonate solution.The two phases are well shaken, the chloroform layer separates, is driedand evaporated. The residue (51.0 g.) consisting mainly of 1-benzyloxy-7-bromo-6-oxo-9 methyl-trans-Decalin (XVI wherein R is CH isused without further purification. The compound can be crystallized fromacetone-hexane and the analytical sample melted at 1l21l3 C.

When 1 benzyloxy-6-oxo-9-ethyl-trans-Decalin (XV wherein R is C H isbrominated in the same way, the product is1-benzy1oxy-7-bromo-6-oxo-9-ethyl-trans- Decalin (XVI wherein R is C Hwhich has melting point 139-140 C.

EXAMPLE Preparation of 1-benzyloxy-6-oxo-9-methyl-A trans-octalin (XVII,R =CH The crude 1-benzyloxy-7-bromo-6-oxo-9-methyl-trans- Decalin (51.0g.) prepared as in Example 19 is dissolved in 600 ml. drydimethylformamide and g. of dry lithium chloride and 35 g. of drylithium carbonate added. The mixture is stirred and heated at refluxunder nitrogen for two hours. The mixture is cooled and most of thesolids removed by filtration. The filtrate is diluted with water andextracted with ether, then ether washed with water, saturated brine,dried and evaporated. The residue is distilled to givel-benzyloxy-6-oxo-9-methyl-A trans-octalin (XVH wherein R is CH as apale yellow oil, boiling point 170 C. at 0.5 mm.

When 1 benzy1oxy-6-oxo-7-bromo-9-ethyl-trans-Decalin (XVI, wherein R isC H is dehydrobrominated as described above, the product is1-benzy1oxy-6-oxo-9- ethyl-A trans-octalin (XVII, wherein R is C I-Iwhich distills at 165 l70 C. at 0.1 mm.

EXAMPLE 21 Preparation of trans J,2,4a,5,6,7,8,8a octahydro 4arrzetlzyl5 t butaxy 2 0x0 1 naplzthaldehyde (XIX, R =CH R=t-butyl) To a stirredsuspension of dry sodium methoxide (from 0.74 g. sodium) in dry benzeneunder nitrogen is added 4.5 ml. of redistilled ethyl formate in a gentlestream. After stirring at room temperature for 0.5 hour, the mixture iscooled to 0 C. and 2.36 g. of 1-t-butoxy-6-oxo- 9-methyl-A-trans-octalin in 20 ml. dry benzene is added dropwise. The solution isthen stirred overnight at room temperature. Water and ether are added tothe mixture. The water is separated and the organic phase extractedtwice with 1 N potassium hydroxide. The combined aqueous phases areacidified with 2.5 M sodium dihydrogen phosphate solution and thoroughlyextracted with ether. The ether is washed with water, saturated brine,dried and evaporated. The residue (2.55 g.) consisting oftrans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-S-t-butoxy-2-oxo-1-naphthaldehyde (XIX wherein R is CH and R is -C(CH is usedwithout further purification.

14 EXAMPLE 22 Preparation of trans 1,2,4a,5,6,7,8,8a octahydro 4amethyl5 benzyloxy 2 0x0 1 naphthaldehyde (XIX, R =CH R'=CH C H The above isprepared from 2.86 g. of crude l-benzyloxy-6-oxo-9-methyl-A' -octalin(XV wherein R is CH and R is CH C H ethylformate (4.5 ml.) and sodiummethoxide (from 0.74 g. sodium) in a manner similar to that describedfor the t-butoxy analog in Example 21. The trans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-5-benzyloxy-Z-oxo-l-naphthaldehyde (XIX whereinR is CH, and R is CH C H (3.1 g.) is obtained as a pale yellow oil andused directly.

When the reactions described in Examples 21 and 22 use as startingmaterial the ethyl analog (R is C H the products are the correspondingethyl compounds.

EXAMPLE 23 Preparation of trans J,2,4a,5,6,7,8,8a octahydro 4amethyl 5 tbatoxy 2 0x0 1 (3 oxobutyl)- I naphthaldehyde (XX, R =CH R=C(CH RII=H)The crude 1-t-butoxy-5-formyl-6-oxo-9-methyl-A' -transoctalin (2.55 g.)is dissolved in ml. dry benzene and the solvent removed to remove tracesof water. This procedure is repeated. The residue is dissolved in 20 ml.dry t-butanol and 0.87 g. freshly distilled methylvinyl ketone added.The air is displaced by nitrogen, the solution cooled down in an icebath and 1 ml. of a 1 M solution of potassium t-butoxide in t-butanol isadded. The solution is left at room temperature overnight. Ether andwater are added and the aqueous phase thoroughly extracted with ether.The ether is washed with water, saturated brine, dried and evaporated.The residue, a viscous pale yellow oil, oftrans-l,2,4a,5,6,7,8,8a-octahy dro-4a-nrethy1-5-t-butoxy2-oxo-1,(3oxobutyD-l-naphthaldehyde (XX, wherein R is CH R is C(CH and R is H) isused without further purification.

EXAMPLE 24 Preparation oftrans-1,2,4a,5,6,7,8,8a-0ctahydro-4a-methyI-S-benzoyloxy-Z-oxo-I-(3-0x0butyl)1 naphthalaehyde R2=CH3, R,'=CH2C5H5, RIG-TH) Fromtrans-l,2,4a,5,6,7,8,8a-octahydro-4a methyl 5-benzyloxy-Z-oxo-l-naphthaldehyde (XIX' wherein R is CH and R is CH C H3.1 g. crude as described in Example 22, 0.87 g. freshly distilledmethylvinyl ketone and 1 ml. of a 1 M solution of potassium t-butoxidein t-butanol there is obtained by following the procedure as describedin Example 23, trans-l,2,4a,5,6,7,8,8a-octahydro-4-a-methyl-5-benzy1oxy-2-oxo- 1- 3-oxobutyl) -1-naphthaldehyde, is obtained as aviscous pale yellow oil which is used without further purification.

When the procedures described in Examples 23 and 24 are carried throughwith the ethyl analog, the products obtained are the 4a-ethylnaphthaldehydes.

EXAMPLE 25 Preparation of trans-1,2,4a,5,6,7,8,8a-0ctaltydro-4a-metyZ-S-benzyloxy-Z-oxo-J-(3-0r0pentyl) l naphthaldehyde (XX, R=CH R'=CH CH R"=CH The above compound is prepared from trans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-5-benzyloxy-2-oxo-1 naphthaldehyde (XIXwherein R is CH and R is CH C H and ethylvinyl ketone by the proceduredescribed in Example 24.

EXAMPLE 26 Preparation 0) methyltrans-1-f0rmyl-I,2,4a,5,6,7,8,8aoctahydro-4a-methyl-5-t-but0xy 5,2 dioxo1 naphthalene-heptanoate (XX, R'=CH R' =C(CH R"=CH CI -I COOCHthoroughly extracted with ether.

The crude trans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-S-t-butoxy-Z-oxo-l-naphthaldehyde prepared in Example 21 is dissolved in5 ml. dry tbutanol and 1.87 g. methyl- 35-oxo-6-heptenoate added. Aftercooling the solution under a nitrogen atmosphere, 1 ml. of a 1 molarsolution of potassium t-butoxide in t-butanol is added and the mix-'-ture kept at room temperature overnight. The solution is diluted withwater and ether and the aqueous phase The ether is Washed with water,and saturated brine, dried and evaporated. 'The residue of methyltrans-l-formyl-l,2,4a,5,6,7,8,8a-='octahydro4a-methyl-S-t-butoxy-6,2-dioxo-1 naphthalenevheptanoate (XXwherein R is CH R is C(CH and 'R is CH CH COOCH is obtained as aviscous, pale jyellow oil, and is used without further purification. Themethyl acetate analog, i.e., where R" is CH COOCH can also be preparedby this procedure using methyl 4- -oxo-5-hexenoate instead of5-oxo-6-heptenoate.

EXAMPLE 27 Preparation of methyl trans-1-f0rmyl-Z,2,4a,5,6,7,8,8a--octalzydro-4a-methyl-5'benzyloxy-5,2-dioxo 1 naphithalene-heptanoate(XX, R =CH R':CH C H R"=CH CH COOCH This is prepared from the crudetrans-1,2,4a,5,6,7,8,8a- 'octahydro-4a-methyl-5-benzyloxy-2-oxo 1naphthaldehyde, 3.1 g., described in Example 22, 1.87 g. of methyl-5-oxo-6-heptenoate and 1 ml. of a 1 M solution of potassium t-butoxidein t-butanol by the procedure described fin Example 26.

The product, methyltrans-l-formyl-1,2,4a,5,6,7,8,8aoctahydro-4a-methyl-5-benzyloxy-6,2-dioxo-1-naphthaldelhyde (XX wherein R is CH R is CH C H and R" is --CH CH COOCHis obtained as a pale yellow viscous oil and was used in this formwithout further purification. 'The methyl acetate analog of the abovecompound, i.e. where R" is CH COOCH can be prepared by this procedurewith methyl 4-oxo-5-hexenoate in place of methyl j-oxo--heptenoate.

EXAMPLE 28 The crude trans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-5-t-butoxy-2-oxo-1-(3-oxobutyl) 1 naphthaldehyde prepared in Example 23is dissolved in 25 ml. dioxan and cooled to C. A solution of 1.7 g.potassium hydroxide in 25 ml. water is added and the air displaced bynitrogen. After standing at room temperature for 3 hours, ether andWater are added to the mixture and the aqueous phase thoroughlyextracted with ether. The ether is washed with water and saturatedbrine, dried and evaporated. The residue is crystallized tromether-hexane. The analytical sample crystallized from hexane has themelting point 134135 C.

EXAMPLE 29 Preparation of (11-85-17enzyl0xy-8aB-metlzyl-4,4a,8,4ba,5,6,7,8,8a-0ctahydr0-2 (3H )-phenanthr0ne (XXI, R =CH R'=CH C H R"=H) Theabove is prepared fromtrans-1,2,4a,5,6,7,8,8aoctahydro-4a-methyl-5-benzyloxy-2-oxo-1(3-oxobutyl)- l-naphthaldehyde (prepared as in Example 24) in 25 ml.dioxan and 1.7 g. potassium hydroxide in 25 ml. Water as described inExample 28. The crude product is chromatographed on alumina to yielddl-8B-benzyloxy-8afimethyl-4-,4afi,4ba,5,6,7,8,8a-octahydro 2(3H)phenanthrone. An analytical sample, recrystallized from methanol, hasmelting point 109-110 C.

1 6 EXAMPLE 30 Preparation ofdZ-8fi-benzyl0xy-8afi-1-dimethyl-4,4afi,4ba, 5,6,7,8,8a octahydro 2(3H)phenanthrone (XXI, R2'=CH3, RICHZCGHS, RIHICH3) This is prepared fromtrans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-5-benzyloxy-2-oxo-1-(3-oxo-pentyl) 1 naphthaldehyde (wherein Ris CH; and R is CH C H by the procedure described in Example 28 to givethe product dl 8B benzyloxy 825,1dimethyl-4,4afi,4ba,5,6,7,8,8aoctahydro-2(3H)-phenanthrone (XXI whereinR is CH R is CH C H and R is CH EMMPLE 31 Preparation oftil-2,3,4,4afl,4aa,5,6,7,8,8a-decahydro-8aotmethyl-8B-t-but0xy-2-0x0phenanthrene1 propionic acid R2ICH3, R,:C(CH3)3, R=CH CH COOH) Crude methyltrans-l-formyl-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-5-t-butoxy-6,2-dioxo-l-naphthaleneheptanoate (3.0 g.) prepared in Example 26 is dissolved in 15 ml. dioxanand 30 ml. of a 1.6 M solution of sodium hydroxide added. The mixture isstirred overnight at room temperature under nitrogen. The solution isdiluted with water and extracted with ether. The aqueous phase isacidified with 6 N sulphuric acid and rapidly extracted with ether. Theether is washed twice with water followed by saturated brine solution.The ether is dried and evaporated.

The residue (2.0 g.) is exhaustively extracted with boiling cyclohexane.The cyclohexane is evaporated and the residue crystallized fromacetonitrile. The analytical sample recrystallized from the same solventhas melting point 8889 C. The acetic acid analog of this compound, whereR" is CH COOH, may be prepared employing the methyl acetate analog ofcompound XX in the reaction.

EXAMPLE 32 Preparation ofdl-2,3,4,4a,8,4ba,5,6,7,8,8a-decahydro'8apmethyl 8Bbenzyloxy-2-oxophenanthrene-1pr0pi0nic acid (XXI, R CH R=CH C H R'"=CHCH COOH) This is prepared from the crude methyl trans-l-formyl-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl 5 benzyloxy-6,2-dioxo-l-naphthaleneheptanoate described in Example 27 in 15 ml. dioxanand 30 ml. of a 1.6 M solution of sodium hydroxide as described inExample 31. The product, dl- 2,3,4,4a,B,4ba,5,6,7,8,8a decahydro 811,8methyLSflbenzyloxy-Z-oxophenanthrene-l-propionic acid is obtained as acrystalline solid. Recrystallization from acetonitrile gives ananalytical sample melting point 158159 C.

EXAMPLE 33 A suspension of 25 mgs. of 2% palladium hydroxide onstrontium carbonate in 5 ml. dry benzene is reduced with hydrogen atatmospheric pressure. When the reduction is complete 54.4 mgs. ofdl-Sfi-t-butoxy-8afl-methyl-4,4a5,4ba,5,6,7,8,8a-octahydro-2(3H)-phenanthrone is added and the reductioncontinued. After 7 minutes, 4.54 ml. of hydrogen has been absorbed andthere is no further absorption. The catalyst is removed by filtrationand the solvent removed under reduced pressure. The residue crystallizedand the solid is recrystallized from hexane at -10 C. to givedl-8fl-t-butoxy-8a 3-methyl-4-,4a,4ba,5, 6,7,8,8a,9,10-decahydro 2(3H)phenanthrone, melting point 97-98 C.

EXAMPLE 34 Preparation of dl-8 8-benzyl0xy-8aB-methyl-4,4a}3,4ba,5,6,7,8,8a,9,10 decahydro-Z (3H )-phenanthr0ne (XXII, R CH R" CH C HR"'=H) Reduction of 43.7 mgs. of 11-8B-benzyloxy-8a,B-methyl-4,4afl,4ba,5,6,7,8,8a octahydro-2(3H)-phenanthrone in benzene with 25mgs. of 2% palladium hydroxide on strontium carbonate as described inExample 33 gives dl-fifl-benzyloxy-Bafi methyl4,4afl,4ba,5,6,7,8,8a,9,10- decahydro-2(3H)-phenanthrone, melting point10l- 102 C.

EXAMPLE 35 Preparation of dl-8/3-benzyl0xy-2,3,4,4afl,4ba,5,6,7,8,8a,9,

10-dodecahydro 811,3 methyl-Z-oxo-phenanthrene-J- propionic acid (XXI',RFCH R'=CH C H R=CH CH COOH) A suspension of 1.0 g. of 2% palladiumhydroxide on strontium carbonate is reduced in 30 ml. water withhydrogen at atmospheric pressure and room temperature. A solution of3.94 g. of dl-SB-benzyloxy-Zfi,4,4afi,4ba,5,6,7,8,8a-decahydro-8a/3-methyl 2 oxo-phenanthrene-lpropionic acid in 10ml. of 1 N sodium hydroxide is added. When 1 molar equivalent ofhydrogen has been absorbed, the catalyst is removed by filtration andthe aqueous phase acidified with dilute hydrochloric acid. The aqueousphase is thoroughly extracted with ether, the ether washed with water,saturated brine, dried and evaporated. The residue (4.0 g.) of crudedl-8,6-benzyloxy-2,3,4,4a;3,4ba, 5,6,7,8,8a,9,10-dodecahydro-8afl-methyl2 oxo-phenanthrene 1 propionic acid is used without furtherpurification.

The procedures detailed in Examples 25 through 35 for the methylcompounds (R is CH in generic formulas are equally useful when (R is C Hand yield the corresponding product. This also applies where R" ismethyl acetate (XX) and following reactions yield (XXI, XXII, and XXIIIA) where R is CH COOH.

EXAMPLE 3 6 Preparation of dl-l 7afi-benzyl0xy-5-hydr0xy-3,5-sec0-4-nr-5(10),9(1I)-D-homoestradien-3-oic acid, 4,5-lactone (XXIII, R =CHR'=CH C H A solution of 4 g. of dl-8B-benzyloxy-2,3,4,4a 3,4bu,5,6,7,8,8a,9,lo-dodecahydro 8nd methyl-Z-oxo-phenanthrene-l-propionic acidin 40 ml. acetic anhydride and 50 mgs. anhydrous sodium acetate isheated under reflux under nitrogen for 4 hours. The solvents areevaporated under reduced pressure and the residue dissolved in ether andwater. The aqueous phase is thoroughly extracted with ether, the etherphases combined and washed successively with 1 M sodium carbonatesolution, water and saturated brine. The ether is separated, dried andevaporated. The residue is crystallized from ether to give dl-l7a3-benzyloxy-5-hydroxy 3,5 seco-4-nor-5(10),9 (11)-D-homoestradien-3-oicacid, 3,5-lactone, melting point 130-131 C.

EXAMPLE 37 Preparation of dI-I7a,6-benzyloxy-5-hydroxy-3,5-seco-4- nor 5D homoestren-3-oic acid, 3,5 lactone (XXIV, R CH R CH C H A suspensionof 0.5 g. of 2% palladium hydroxide on strontium carbonate in 40 ml. drybenzene is reduced with hydrogen at room temperature and atmosphericpressure. Then 1.76 g. of dl-l7afi-benzyloxy-5-hydroxy-3,5-seco-4-nor-5( 10) ,9 1 l -D-homoestradien-3-oic acid, 3,5 -lactone in 40 m1. ofdry benzene is added and the reduction continued. During 22 hours, 135ml. of hydrogen had been absorbed and the catalyst is then removed byfiltration and the solvent evaporated. The residue is dissolved in etherand percolated through a plug of florisil. The fiorisil is washed withmore ether and the combined ether solutions evaporated and the residuecrystallized from an ether-hexane mixture to givedl-17a/3-benzyloxy-5-hydroxy-3,5-seco-4-nor-5(10)-D-homoestren-3-oicacid, 3-5- lactone, melting point 123-124" C.

1 :8 EXAMPLE 38 A solution of 0.5 g. dl 17a 3 benzyloxy 5 hydroxy 3,5seco 4 nor 5(10) D homoestren-3-oic acid, 3,5-lactone in ml. ether and30 m1. benzene is cooled to -50 C. under nitrogen and 2 ml. of a 3 Msolution of methyl magnesium bromide in ether is added with stirringover 20 minutes. After stirring a further 1 hour at -50 C., 2 Nhydrochloric acid is added and the mixture warmed to room temperature.The organic phase is diluted with benzene and the aqueous phasethoroughly extracted. The organic phase is washed with a 1 M sodiumcarbonate solution, water, dried and evaporated to give 0.55 g. of acolorless oil. The oil is dissolved in 15 ml. glacial acetic acid and1.5 ml. concentrated hydrochloric acid is added. The solution is allowedto stand under nitrogen at room temperature for 48 hours. The solventsare removed under reduced pressure and the residue dissolved in benzene.The benzene is washed with saturated sodium bicarbonate, water,saturated brine, dried and evaporated to give a crystalline residue.This is recrystallized from ethanol-to give 300 mgs.l9-nor-D-homotestosterone, benzyl ether, melting point 188 C. A puresample is prepared by recrystallization from a chloroform-ethanolmixture. The analytical sample has melting point 194-195 C.

The procedures outlined in Examples 36, 37 and 38 are equally applicablewhen R in the generic formula is ethyl. In this instance the productsare the corresponding ethyl compounds.

I claim:

1. A compound of the formula:

when'n R is selected from the group consisting of methyl and ethyl and Ris selected from the group consisting of t-butyl and benzyl.

2. A compound of the formula:

wherein R is selected from the group consisting of methyl and ethyl andR' is benzyl.

4. The compound dl l7a 3 benzyloxy 5 a hydroxy- 3,5-seco-4-nor-5 10) ,91 1 -D-hornoestradien-3-oic acid, 3,5-lactone.

5. The compound d1 l7a 3-t-butyloxy 5 hydroxy- 3,5 -seco-4-nor-5(10),9(11)-D-hornoestradiene-3-oic acid, 3,5-lactone.

6. The compound dl-17afi benzyloxy-l3-ethyl-5-hydroxy-3,5-seco-4 nor 510),9(l1)-D-homogonadiene-3- oic acid, 3,5-lactone.

7. The compound dl-17a5-t-butoxy-13-ethyl-5-hydroxy- 3,5-seco-4-nor-5 l),9 (1 l -D-homogonadiene-3-oic acid, 3,5-lactone.

8. The compound dl 17a}? benzyloxy hydroxy- 3,5-seco-4-nor-5()-D-homostren-3-oic acid, 3,5-lactone.

9. The compound d1 1711B t butyloxy-S-hydroxy-3,5-seco-4-nor-5(l0)-D-homoestrene-3-oic aicid, 3,5-1actone.

10. The compound d1-17a/3benzyloxy-l3-ethyl-5-hydroxy-3,5-seco-4-nor-5(l0)-D-homogonene 3 oicacid, 3,5-lactone.

11. The compound d117aB-t-butoxy-13-ethy1-5-hydroxy-3,5-seco-4-nor-5(l0)-D-homogonene 3 oicacid, 3,5-lactone.

12. The compound di-17-a-benzyloxy-S-keto-C-homoestra-4-ene.

13. The compound 17a 3-benzyloxy-IB-ethyl-D-homogon-4-ene-3-one.

14. A process for the preparation of compound of the formula:

wherein R is selected from the group consisting of methyl and ethyl andR is selected from the group consisting of t-butyl and benzylcomprising, treating a compound of the formula wherein R is selectedfrom the group consisting of methyl and ethyl, R is selected from thegroup consisting of t-butyl and benzyl and R is propionic acid, withacetic at elevated temperatures anhydride and sodium acetate under aninert atmosphere and separating a compound of the formula:

wherein R and R are as described above, from said mixture; contactingthe latter product with hydrogen in the presence of an inert organicsolvent and a palladium on strontium carbonate catalyst, separating aproduct of the formula:

wherein R and R are as described above, from the reaction mixture;treating the product with an alkyl magnesium halide and anacetic-hydrochloric acid mixture and recovering the desired product fromthe mixture.

15. A process for the preparation of a compound of the formula:

wherein R is selected from the group consisting of methyl and ethyl andR is a member selected from the group consisting of t-butyl and benzylcomprising, treating a compound of the formula:

wherein R and R are as described above and R is propionic acid, withacetic anhydride and anhydrous sodium acetate at elevated temperaturesunder an inert atmosphere and recovering the product from the reactionmixture.

16. A process for the preparation of a compound of the formula:

wherein R is selected from the group consisting of methyl and ethyl andR is selected from the group consisting of 't-butyl and benzylcomprising, treating a compound of the formula:

wherein R and R are as described above, with hydrogen in the presence ofan inert organic solvent and a palladium on strontium carbonate catalystunder an inert atmosphere and recovering the product from the reactionmixture.

21 22 17. A process for the preparation of a compound of the formula: OR

OR Q E I 10 i wherein R and R are as described above, with a methyl Tmagnesium halide and a m'urture of acetic and hydrochloric acid atreduced temperatures and recovering the formed product from the reactionmixture.

No references cited.

wherein R is selected from the group consisting of methyl and ethyl andis benzyl comprising treating a WALTER A. MODANCE, Primary Exammer.pound of the formula: JAMES A. PATTEN, Assistant Examiner.

1. A COMPOUND OF THE FORMULA: